CDC42EP5/BORG3 modulates SEPT9 to promote actomyosin function, migration, and invasion

Abstract

Fast amoeboid migration is critical for developmental processes and can be hijacked by cancer cells to enhance metastatic dissemination. This migratory behavior is tightly controlled by high levels of actomyosin contractility, but how it is coupled to other cytoskeletal components is poorly understood. Septins are increasingly recognized as novel cytoskeletal components, but details on their regulation and contribution to migration are lacking. Here, we show that the septin regulator Cdc42EP5 is consistently required for amoeboid melanoma cells to invade and migrate into collagen-rich matrices and locally invade and disseminate in vivo. Cdc42EP5 associates with actin structures, leading to increased actomyosin contractility and amoeboid migration. Cdc42EP5 affects these functions through SEPT9-dependent F-actin cross-linking, which enables the generation of F-actin bundles required for the sustained stabilization of highly contractile actomyosin structures. This study provides evidence that Cdc42EP5 is a regulator of cancer cell motility that coordinates actin and septin networks and describes a unique role for SEPT9 in melanoma invasion and metastasis.

Cellular functions of actin- and microtubule-associated septins

“…two of which involve interactions with actin surface domains that are also bound by the ATP-bound myosin V subfragment 1 and the actin-severing protein cofilin (Figure 3A) 36 . In contrast to these findings of direct septin-actin binding, septin association with actin is also mediated by anillin 50 , non-muscle myosin II 57 , and effectors of the small GTPases Cdc42 (Cdc42EP/Borg) and Rho (Rhotekin) (Figure 3B) 51,[58][59][60] . These factors recruit septins to actin or associate with septins and actin synergistically.…”

“…Septins are essential for the migration of many cell types, including epithelia, fibroblasts, lymphocytes and neurons 53,[86][87][88] . Importantly, abnormalities in septin expression enhance the migratory and invasive properties of cancer cells 9,38,56,60,89,90 . Depending on the cell type and mode of cell migration (that is, amoeboid or mesenchymal), septins regulate the organization and contractility of actomyosin on stress fibers and/or the plasma membrane (Figure 4).…”

“…In mouse melanoma cells with an amoeboid mode of migration, Sept9 is the only septin paralog whose upregulation correlates with the invasive metastatic phenotype 60 . The rounded amoebalike morphology of these cells is sustained by contractile actomyosin filaments that associate with the plasma membrane 60 .…”

“…In mouse melanoma cells with an amoeboid mode of migration, Sept9 is the only septin paralog whose upregulation correlates with the invasive metastatic phenotype 60 . The rounded amoebalike morphology of these cells is sustained by contractile actomyosin filaments that associate with the plasma membrane 60 . The cortical actomyosin network depends on Sept9 and Cdc42EP5 (BORG3), which localizes preferentially to the cell cortex with actin and phosphorylated (pSer19) myosin regulatory light chain 60 .…”

A Cdc42-Borg4-Septin 7 axis regulates HSCs polarity and function

“…It is likely that this axis is specific for HSCs, and that thus other cells or cell types might regulate and use borg-septin interactions differentially, with distinct combinations affecting distinct cytoskeletal/nuclear structures. For example borg3 acts via septin 9 to control actomyosin function and cancer cell invasion (Farrugia et al , 2020), and a Cdc42-borg2-septin 2 axis activates the DNA damage response in cell lines (Eduardo da Silva et al , 2020). It remains to be further investigated whether other types of stem cells will rely on a similar axis, or whether distinct types of stem cells will use type-specific combinations of borgs and septins to link Cdc42 activity to changes in the septin network.…”